This proposal investigates the mechanisms by which goblet cells maintain immune tolerance in the conjunctiva. Dry eye is one of the most prevalent medical conditions that decreases quality of life due to irritation symptoms and visual disturbance at a great cost to society. A hallmark of aqueous tear deficiency is loss of conjunctival goblet cells. It is recognized that goblet cell secretions are essential for maintaining a stable tear film and our preliminary data indicates that goblet cells also suppress dendritic cell maturation and condition them with retinoic acid metabolizing activity to promote tolerance and ocular surface immune homeostasis. Additionally, passage of ocular surface antigens through conjunctival goblet cells under cholinergic regulation promotes immune tolerance. Goblet cell dysfunction/loss increases DC maturation and disrupts tolerance induction. Two specific aims in this proposal investigate these novel hypotheses in mouse models and confirm their relevance in humans. The proposed experiments investigate these novel and previously unrecognized immunoregulatory functions for conjunctival goblet cells. At the conclusion of this project, we will better understand the mechanisms by which goblet cells condition dendritic cells towards a tolerogenic state and direct presentation of ocular surface antigens to maintain tolerance. The end product of this project will be a fundamental new understanding of conjunctival immunoregulation and novel strategies to maintain or duplicate goblet cell immunoregulatory function in dry eye disease.